Drug-induced regulatory overcompensation has motivational consequences: Implications for homeostatic and allostatic models of drug addiction

Initial administration of 60% nitrous oxide (N(2)O) at 21°C ambient temperature reduces core temperature (Tc) in rats, but tolerance develops to this hypothermic effect over several administrations. After additional N(2)O administrations, a hyperthermic overcompensation (sign-reversal) develops such that Tc exceeds control levels during N(2)O inhalation. This study investigated whether rats would employ behavioral thermoregulation to facilitate, or oppose, a previously acquired hyperthermic overcompensation during N(2)O administration. To establish a hyperthermic sign-reversal, male Long-Evans rats (N = 12) received 10 3-h administrations of 60% N(2)O while housed in a gas-tight, live-in, “inactive” thermal gradient (∼21°C). Following the tenth N(2)O exposure, the thermal gradient was activated (range of 10–37°C), and rats received both a control gas session and a 60% N(2)O test session in counterbalanced order. Mean Tc during N(2)O inhalation in the inactive gradient was reliably hypothermic during the first exposure but was reliably hyperthermic by the tenth exposure. When subsequently exposed to 60% N(2)O in the active gradient, rats selected a cooler Ta, which blunted the hyperthermic sign-reversal and lowered Tc throughout the remainder of the N(2)O exposure. Thus, autonomic heat production effectors mediating the hyperthermia were opposed by a behavioral effector that promoted increased heat loss via selection of a cooler ambient temperature. These data are compatible with an allostatic model of drug addiction that suggests that dysregulatory overcompensation in the drugged-state may motivate behaviors (e.g., drug taking) that oppose the overcompensation, thereby creating a vicious cycle of escalating drug consumption and recurring dysregulation.